This competitive renewal application is based on the discovery that the env gene of HERV-K18 (Human Endogenous Retrovirus) encodes a superantigen, which is transcriptionally activated by EBV (Epstein-Barr Virus) and IFN-alpha (type I interferon). The working hypothesis is that the T cell stimulation elicited by the superantigen is not only essential for establishing life-long persistent infection with EBV in healthy individuals, but also plays a crucial role in EBV-associated diseases and malignancies. The following specific aims are proposed to test this model: I) The control of HERV-K18 expression will be defined. The role of CD21 engagement in the initiation of superantigen expression will be analyzed, based on the observation that IFNalpha and EBV infection lead to superantigen expression, both acting through CD21 on resting B cells. Furthermore, the role of EBV LMP-2A in sustained superantigen expression will be evaluated, based on the finding that this EBV latent gene product is sufficient to transactivate HERV-K18 env, leading to superantigen activity. II) HERV-K18 superantigen-reactive cells will be delineated in vivo and in vitro. For this purpose, an HLA.DR/HERV-K18 Env tetramer will be constructed to identify and stimulate superantigen-reactive T cells. The recent discovery of the murine TCR (T cell receptor) Vbeta specificity for the human superantigen will be exploited to define and map the TCR-superantigen interaction site. In addition, the role of CD48 in the superantigen-induced T cell activation will be tested, since EBV upregulates expression of this co-stimulatory molecule. III) The role of the HERV-K18 superantigen in EBV-infection will be determined, because the central dogma of this proposal is that the superantigen activity is required for the successful EBV life-cycle in the human host. In vitro and in vivo EBV-infection/ outgrowth/ persistent latency/lytic cycle/reactivation models will be used to address this aim. IV) The DNA of patients suffering from EBV-associated diseases will be typed for preferential expression of certain HERV-K18 alleles, compared to their respective healthy controls. This aim is based on the observation that the 3 HERV-K18 env alleles defined so far are unequally distributed in the Caucasian population and differ in their superantigen expression level. Collectively, these studies will further the general understanding of how viruses exploit the immune system of their hosts to their own advantage.